1,4-Methano-2-benzazepine derivatives useful as cerebal dysfunction-improving drugs, anti-convulsant, anti-epileptic or anti-anxiety drugs

ABSTRACT

1,4-Methano-2,3,4,5-tetrahydro-1H-2-benzazepin-3-one derivatives of the formula: ##STR1## wherein X is halogen, n is 1 or 2, and R is hydrogen, lower alkyl or phenyl-lower alkyl. They are useful as medicaments, e.g. cerebral dysfunction-improving drugs, anti-convulsants, anti-epileptics and anti-anxiety drugs.

TECHNICAL FIELD AND DISCLOSURE OF INVENTION

This invention relates to novel and therapeutically useful1,4-methano-2,3,4,5-tetrahydro-1H-2-benzazepin-3-one derivativesrepresented by the formula: ##STR2## wherein X is halogen (fluorine,chlorine, bromine or iodine), n is 1 or 2 and R is hydrogen, lower alkyl(methyl, ethyl, propyl, isopropyl, butyl, etc.) or phenyllower alkyl(benzyl, phenethyl, etc.).

Japanese Patent Publication No. 43-22097 (1968), Chem. Pharm. Bull., 14,324 (1966) and J. Med. Chem., 21, 1105 (1978) mention compounds of theformula: ##STR3## wherein X' is hydrogen or methoxy, which compounds areuseful as an intermediate for the synthesis of certain analgesics.

The present inventors have synthesized various compounds having a moietyof 5-membered ring lactam formed by intramolecular ring-closure ofgamma-aminobutyric acid (hereinafter abbreviated as GABA) in theirstructure to investigate their utility. As a result, it has been foundthat the compounds of the invention have potent antagonistic activitiesagainst lethality and convulsions induced by GABA antagonist such aspicrotoxin or bicuculline and accordingly, GABA-like activities. GABAper se is considered to be difficult to transmit blood-brain barrierwhen administered peripherally, so that effects on the central nervoussystem can be little expected. On the contrary, the compounds of theinvention have the aforementioned effects even when orally administeredand so are highly useful.

Further, the compounds of the invention have antielectroshock andantimetrazole actions or electrocorticogram-improving action in atemporary cerebral ischemia model, antihypoxia action and the like.Thus, they are also useful as drugs for improving cerebral dysfunction,anticovulsants, antiepileptics, antianxiety drugs, or other medicaments.

On the other hand, the known compounds mentioned above are extremelyweak in such actions as compared with the compounds of the invention orpractically ineffective in such actions.

The compounds of Formula (I) can be produced by subjecting an oximecompound of the formula: ##STR4## to reducing followed by ring-closureof the resulting product, wherein X and n are the same as defined above,and R¹ is hydrogen or lower alkyl.

The reaction is preferably catalytic reduction, which is carried out inthe presence of a metallic catalyst such as Reney nickel, platinum oxideor palladium carbon, in an inert solvent preferably lower alkanol suchas methanol or ethanol or lower alkanoic acid such as acetic acid, ifdesired in the presence of ammonia for the prevention of possiblepolymerization, at a temperature of from room temperature to 150° C,preferably 50° to 100° C., under an ordinary pressure or 50 to 150 atmof hydrogen. Hydrogen or hydrazine may be used as a source of hydrogen.The reduction can also be carried out by the use of sodium in liquidammonia containing methanol or by the use of a metal such as zinc or tinand an acid such as hydrochloric acid or acetic acid.

Where the reaction is carried out over about 60° C., there can beobtained the objective compounds of the formula: ##STR5## wherein X andn are the same as defined above, without isolating the intermediate ofthe formula: ##STR6## wherein X, n and R¹ are the same as defined above.

Otherwise, the intermediate can be isolated and then converted into thecompound (Ia) by heating at 60°-200° C.

The compound of Formula (III) in trans-form does not participate in thering-closure reaction, but can be separated by extraction with an acidor alkali.

The compound of Formula (Ia) is allowed to react with an alkylatingagent such as dimethyl sulfate, diethyl sulfate or a compound of theformula:

    R.sup.2 --Y                                                (IV)

wherein R² is lower alkyl or phenyl-lower alkyl, and Y is a reactiveresidue such as halogen, methylsulfonyloxy or p-tolylsulfonyloxy, togive the objective products of the formula: ##STR7## wherein X, n and R²are the same as defined above.

The reaction is carried out by treating the compound (Ia) with an alkalimetal compound such as lithium hydride, sodium hydride, potassiumhydride, sodium amide, diisopropylaminolithium, sodium methoxide orsodium ethoxide, in an inert solvent such as benzene, toluene,tetrahydrofuran, dioxane, dimethylformamide or dimethyl sulfoxide, thenwith an alkylating agent, usually at 0° C. to the refluxing temperatureof the solvent for several hours.

The compounds of Formula (I) can also be prepared by subjecting acompound of the formula: ##STR8## to catalytic reduction, wherein X, nand R¹ are the same as defined above, in the coexistence of an amine ofthe formula:

    R--NH.sub.2                                                (VI)

wherein R is the same as defined above, if necessary followed byring-closure under heating.

The pharmacological properties of the compounds of the invention areshown below.

Test Method 1. Anti-picrotoxin Action

Groups each of 7-14 male dd mice were used. A test compound was orallyadministered and 60 minutes thereafter, picrotoxin (5 mg/kg) wasadministered subcutaneously. The 50% anti-lethal dose (ED₅₀) wascalculated from the servival rate within 30 minutes.

2. Anti-bicuculline Action

Groups each of 4-14 male dd mice were used. Each test compound wasadministered orally and 60 minutes thereafter, bicuculline (0.6 mg/kg)was administered intravenously. The dose (ED₅₀) required for 50%suppression of the occurrence of tonic-extensile convulsions within 5minutes against the control group was determined.

    ______________________________________                                        Results                                                                                                  Anti-bicuculline-                                  Test       Anti-picrotoxin-lethal                                                                        convulsive action,                                 Compound   action, ED.sub.50 mg/kg, p.o.                                                                 ED.sub.50 mg/kg, p.o.                              ______________________________________                                        A          62              95                                                 B          66              45                                                 C          50              73                                                 D(Comparison)                                                                            1100            >1000                                              E(Comparison)                                                                            >100 (0%)       >100 (0%)                                          ______________________________________                                         A: Compound of Example 1                                                      B: Compound of Example 2                                                      C: Compound of Example 3                                                      D: 1,4Methano-2,3,4,5-tetrahydro-1H--2benzazepin-3-one (known compound)       E: 8Methoxy-2-methyl-1,4-methano-2,3,4,5-tetrahydro-1H--2-                    benzazepin3-one (known compound)                                         

The compounds of Formula (I) of the invention, when used as medicines,can be administered orally or parenterally in the form of pharmaceuticalagent in combination with a pharmaceutically acceptable and suitablecarrier. The pharmaceutical agent may take any conventional form such astablets, capsules, granules, powders, injectable solutions, etc. Thedaily dose for human adults usually ranges from about 10 mg to about 500mg for oral administration, in single or multiple doses, but the dosagemay vary depending upon the age, the weight and/or the conditions of apatient to be treated and the response to the medication.

The invention will be explained more concretely by the followingexamples, but they are not to be construed as limiting the presentinvention.

EXAMPLE 1

A solution of 80 g of methyl 6-chloro-4-hydroxyimino-1,2,3,4-tetrahydro-2-naphthoate in a mixture of 1liter of methanol and 100 ml of 10% ammonia-methanol is placed in anautoclave and 10 g of Raney nickel catalyst is added. An initialhydrogen pressure of 60 atm is applied, and the catalytic reduction iscarried out at 60°-70° C. for 3 hours. After the reactant is allowed tocool, the catalyst is filtered off, the filtrate is concentrated, andthe residual oil is extracted with chloroform. The chloroform layer iswashed with aqueous potassium carbonate solution followed by water anddried over sodium sulfate, and the chloroform is distilled off. Theresidue is heated at 120° C. on an oil bath for 2 hours and thendissolved in chloroform. The solution is washed with 5% hydrochloricacid and dried over sodium sulfate, and the solvent is distilled off.The residual solid is recrystallized from a mixture of ether and acetoneto give 25 g of8-chloro-1,4-methano-2,3,4,5-tetrahydro-1H-2-benzazepin-3-one, m.p.212°-215° C., in the form of colorless crystals.

EXAMPLE 2

To a solution of 2 g of8-chloro-1,4-methano-2,3,4,5-tetrahydro-1H-2-benzazepin-3-one in 15 mlof dimethylformamide is added gradually 1 g of 50% sodium hydride (inmineral oil) under ice-cooling. The mixture is then stirred at 40°-50°C. for 1 hour. It is again cooled in an ice-bath, and 3 g of methyliodide is added dropwise. The reactant solution is then stirred at roomtemperature for 3 hours. The reaction mixture is poured into icecoldwater, neutralized with dilute hydrochloric acid, and extracted withethyl acetate. The organic layer is washed with water and dried, and thesolvent is distilled off. When the residual oil is treated with hexane,crystallization takes place. The crystalline product thus obtained iscollected by filtration and recrystallized from a mixture of isopropylether and hexane to give 1.5 g of8-chloro-2-methyl-1,4-methano-2,3,4,5-tetrahydro-1H-2-benzazepin-3-one,m.p. 88°-91° C., in the form of colorless crystals.

EXAMPLE 3

A solution of 14.4 g of methyl5,7-dichloro-4-hydroxyimino-1,2,3,4-tetrahydro-2-naphthoate in a mixtureof 80 ml of acetic acid and 100 ml of methanol is charged in anautoclave. Platinum oxide catalyst, 0.8 g, is added and reduction iscarried out under an initial hydrogen pressure of 40 atm and 40°-50° C.for 7 hours. After the reactant is allowed to cool, the catalyst isfiltered off, and the filtrate is concentrated under reduced pressure.The residual oil is dissolved in chloroform. The solution is washed withaqueous potassium carbonate solution followed by water and dried oversodium sulfate, and the chloroform is distilled off. The residualsemi-solid is heated at 110°-120° C. on an oil bath for 2 hours and thencooled. The resulting product is crystallized with ethyl acetate. Thecrystalline product thus obtained is collected by suction filtration andrecrystallized from a mixture of ethyl acetate and ethanol to give 4.7 gof 6,8-dichloro-1,4-methano-2,3,4,5-tetrahydro-1H-2-benzazepin-3-one,m.p. 186°-188° C., in the form of colorless crystals.

The following compounds are produced in the same procedure as the aboveExamples.

4. 6-Chloro-1,4-methano-2,3,4,5-tetrahydro-1H-2-benzazepin-3-one, m.p.187°-189° C.

5.6-Chloro-2-methyl-1,4-methano-2,3,4,5-tetrahydro-1H-2-benzazepin-3-one,m.p. 137°-139° C.

6. 7-Chloro-1,4-methano-2,3,4,5-tetrahydro-1H-2-benzazepin-3-one, m.p.120°-123° C.

7.2-Butyl-8-chloro-1,4-methano-2,3,4,5-tetrahydro-1H-2-benzazepin-3-one,m.p. 75°-77° C.

8.8-Chloro-2-phenethyl-1,4-methano-2,3,4,5-tetrahydro-1H-2-benzazepin-3-one,m.p. 113°-115° C.

9. 8-Fluoro-1,4-methano-2,3,4,5-tetrahydro-1H-2-benzazepin-3-one, m.p.203°-205° C.

10.8-Fluoro-2-methyl-1,4-methano-2,3,4,5-tetrahydro-1H-2-benzazepin-3-one,m.p. 120°-123° C.

11. 6,7-Dichloro-1,4-methano-2,3,4,5-tetrahydro-1H-2-benzazepin-3-one,m.p. 196°-200° C.

12.6,7-Dichloro-2-methyl-1,4-methano-2,3,4,5-tetrahydro-1H-2-benzazepin-3-one,m.p. 148°-150° C.

13. 7,8-Dichloro-1,4-methano-2,3,4,5-tetrahydro-1H-2-benzazepin-3-one,m.p. 215°-217° C.

14.7,8-Dichloro-2-methyl-1,4-methano-2,3,4,5-tetrahydro-1H-2-benzazepin-3-one,m.p. 134°-136° C.

15. 8-Bromo-1,4-methano-2,3,4,5-tetrahydro-1H-2-benzazepin-3-one.

The invention has been disclosed fully in the description given aboveincluding Examples, but various alterations and modifications can bemade without departing from the spirit and scope of the invention.

We claim:
 1. 1,4-Methano-2,3,4,5-tetrahydro-1H-2-benzazepin-3-onecompounds represented by the formula: ##STR9## wherein X is halogen, nis 1 or 2, and R is hydrogen, lower alkyl or phenyl-lower alkyl.
 2. Acompound of claim 1:8-chloro-1,4-methano-2,3,4,5-tetrahydro-1H-2-benzazepin-3-one.
 3. Acompound of claim 1:8-chloro-2-methyl-1,4-methano-2,3,4,5-tetrahydro-1H-2-benzazepin-3-one.4. A compound of claim 1:6,8-dichloro-1,4-methano-2,3,4,5-tetrahydro-1H-2-benzazepin-3-one.
 5. Acompound of claim 1:6-chloro-1,4-methano-2,3,4,5-tetrahydro-1H-2-benzazepin-3-one.
 6. Acompound of claim 1:6-chloro-2-methyl-1,4-methano-2,3,4,5-tetrahydro-1H-2-benzazepin-3-one.7. A compound of claim 1:7-chloro-1,4-methano-2,3,4,5-tetrahydro-1H-2-benzazepin-3-one.
 8. Acompound of claim 1:8-fluoro-1,4-methano-2,3,4,5-tetrahydro-1H-2-benzazepin-3-one.
 9. Acompound of claim 1:8-fluoro-2-methyl-1,4-methano-2,3,4,5-tetrahydro-1H-2-benzazepin-3-one.10. A cerebal dysfunction-improving, anti-convulsant, anti-epileptic oranti-anxiety composition comprising a effective amount of said compoundof claim 1 and a pharmaceutically acceptable carrier.